Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:3]([CH3:11])[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(C(C)=O)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-hydroxy-3-methylphenyl)ethanone (5 g, 33.3 mmol), ethyl 2-bromoacetate (1.1 eq.), and cesium carbonate (2 eq.) in acetonitrile (200 mL) was stirred at room temperature overnight. The acetonitrile was removed in vacuo, and the crude oil was dissolved in ethyl acetate (50 mL) and washed with 1M HCl (2×50 mL), water (2×50 mL), and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to obtain ethyl 2-(4-acetyl-2-methylphenoxy)acetate (683).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7](Br)[C:6]([F:11])=[C:5]([F:12])[C:3]=1[NH2:4].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.C(O)C>[F:1][C:2]1[C:8]([F:9])=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]([F:11])=[C:5]([F:12])[C:3]=1[NH2:4]
Reactant: OB(O)c1ccccc1
Reactant: Nc1c(F)c(F)c(Br)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: Nc1c(F)c(F)c(-c2ccccc2)c(F)c1F
Temperature: 25 °C

Procedure:
2,3,5,6-Tetrafluoro-4-bromoaniline (13.8 g, 56.7 mmol) is dissolved in benzene (200 mL) and treated with 1.5 equivalents of phenylboronic acid (10.4 g, 85.1 mmol) and a catalytic amount of tetrakistriphenylphosphine palladium(0) (4.2 g, 3.6 mmol) as a solution in ethanol (30 mL). Sodium carbonate (60 mL of 2 M aqueous solution) is added and the reaction mixture stirred and heated to reflux temperature for 24 hours. After cooling to room temperature the mixture is partitioned between Et2O (500 mL) and water (250 mL). The organic layer is washed with brine, dried (MgSO4) and concentrated by rotary evaporator. The residual oil is purified by flash chromatography (9:1 hexanes/EtOAc) to give 2,3,5,6-tetrafluoro-4-phenylaniline as an oil.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:19])=[C:6]([CH:11]=[C:12]([Cl:18])[C:13]=1[NH:14][C:15](=[O:17])[CH3:16])[C:7]([O:9][CH3:10])=[O:8])[CH:2]=[CH2:3].[H-].[Na+].S(OC)(O[CH3:26])(=O)=O>CN(C=O)C>[CH2:1]([C:4]1[C:5]([O:19][CH3:26])=[C:6]([CH:11]=[C:12]([Cl:18])[C:13]=1[NH:14][C:15](=[O:17])[CH3:16])[C:7]([O:9][CH3:10])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)c(C(=O)OC)cc(Cl)c1NC(C)=O
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCc1c(NC(C)=O)c(Cl)cc(C(=O)OC)c1OC
Reaction time: 0.25 h

Procedure:
A mixture of the phenolic compound of step 6 above (4 g) and NaH (0.7 g) in DMF (50 ml) is stirred for 15 minutes. Dimethyl sulfate (2 g) is added and the mixture is stirred for 16 hours. The mixture is partitioned between CH2Cl2 and H2O, and the organic layer is separated and washed with H2O, dried (MgSO4) and evaporated. The solid residue is twice recrystallized from MeOH-H2O and chromatographed on silica gel affording the desired product which is used in the next step.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1.C1(C=CC=C(O)C=1)O.C(O[C:41]1[CH:57]=[CH:56][C:44]([C:45]([O:47]C2C=CC(C=O)=CC=2)=[O:46])=[CH:43][CH:42]=1)CCCCCCCC=C.[O-]Cl=O.[Na+]>>[CH2:11]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:19][C:41]2[CH:57]=[CH:56][C:44]([C:45]([OH:47])=[O:46])=[CH:43][CH:42]=2)=[O:18])=[CH:15][CH:14]=1)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2]
Reactant: C=CCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Reactant: O=C(O)c1ccc(OCCCCCCCCCCBr)cc1
Agent: Oc1cccc(O)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Product: C=CCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1

Procedure:
Synthesized as described above for compound 7. Quantities: resorcinol (2.11 g, 19.1 mmol), 12 (5.6 g, 14.7 mmol), NaH2PO4·H2O (6.89 g, 44.2 mmol), NaClO2 (7.72 g, 85.4 mmol). Yield 5.8 g (quant). 1H NMR: δH (CDCl3; 300 MHz): 1.27-1.57 (10 H, m, CH2), 1.85 (2 H, m, O—CH2—CH2), 2.08 (2 H, m, CH2═CH—CH2), 4.07 (2 H, t, 3J=6.6 Hz, O—CH2), 4.99 (2 H, m, CH2═CH), 5.84 (1 H, m, CH2═CH), 7.00 (2 H, d, 3J=8.9 Hz, Ar—H), 7.36 (2 H, d, 3J=8.6 Hz, Ar—H), 8.17 (2 H, d, 3J=8.9 Hz, Ar—H), 8.22 (2 H, d, 3J=8.6 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 26.4, 29.3, 29.4, 29.5, 29.7, 29.8, 34.2, 68.7, 114.6, 114.8, 121.34, 122.4, 127.0, 132.8, 139.5, 156.0, 164.2, 164.7, 171.7.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][NH:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[NH2:18])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(N(CC)CC)C.[Cl-].C([O:29][C:30](=O)[C:31](O)=[O:32])C>O1CCCC1>[CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:11]2[C:12](=[CH:13][CH:14]=[C:15]([F:17])[CH:16]=2)[NH:18][C:30](=[O:29])[C:31]1=[O:32])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(CNc1cc(F)ccc1N)OCC
Reactant: CCOC(=O)C(=O)O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2ccc(F)cc21)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
660 mg of N(-2-amino-5-fluorophenyl)-aminomethanephosphonic acid diethyl ester is introduced in 70 ml of absolute tetrahydrofuran with 509 mg of triethylamine. A solution of 685 mg of oxalic acid ethyl ester chloride in 30 ml of tetrahydrofuran is slowly instilled into this solution. The batch is stirred for 4 hours at room temperature. After suctioning-off of the precipitated salts, the filtrate is concentrated by evaporation, boiled in a mixture of 23 ml of ethanol and 23 ml of 1N hydrochloric acid for 2 hours at 110° C. bath temperature. It is evaporated to dryness and the residue is chromatographed on silica gel with methylene chloride:ethanol=10:1. 561 mg of (7-fluoro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)-methanephosphonic acid diethyl ester is obtained.
Reaction SMILES: CC1(C)[O:10][C@H:9]2[C@H:4]([C@@H:5]([CH2:16][OH:17])[O:6][C@@H:7]3[O:13]C(C)(C)[O:11][C@@H:8]32)[O:3]1.[C:19](O)(=[O:42])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]#[C:29][C:30]#[C:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:19]([O:17][CH2:16][CH:5]1[CH:4]([OH:3])[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:13])[O:6]1)(=[O:42])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]#[C:29][C:30]#[C:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CC1(C)O[C@H]2[C@@H](O1)[C@@H](CO)O[C@@H]1OC(C)(C)O[C@@H]12
Reactant: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)OCC1OC(O)C(O)C(O)C1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,2;3,4-di-O-isopropylidene-D-galactopyranose (2.6 g, 10 mmol) and 10,12-tricosadiynoic acid (3.5 g, 10 mmol) were dissolved in 25 ml methylene chloride. 1-Ethyl-3(3-dimethylaminopropyl)carbodiimide (2 g, >10 mmol) was added neat. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted to 100 ml, extracted with water (2×25 ml), dried over MgSO4 and the solvent was removed in vacuo. The crude product was treated with trifluoroacetic acid (10 ml) at room temperature for 30 minutes, evaporated in vacuo, and purified by straight phase chromatography on a CHROMATOTRON, eluted with methanol/chloroform (5:95). The product was characterised by NMR.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:15])[CH2:13]Br)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1>C(#N)C>[N:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH2:13][C:12]([N:9]3[CH2:10][CH2:11][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]3)=[O:15])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CCOC(=O)C1CCN(C(=O)CBr)CC1
Solvent: CC#N
Product: CCOC(=O)C1CCN(C(=O)CN2CCN(c3ccncc3)CC2)CC1
Reaction time: 3 h
Yield: 32.4 %

Procedure:
A solution of ethyl-1-(bromoacetyl)-piperidin-4-carboxylate (0.84 g, 3 mMoles) in acetonitrile (10 ml) was added dropwise to a stirred solution of 1-(4-pyridyl)piperazine (0.5 g, 3 mMoles) in acetonitrile (20 ml) and the resulting mixture was allowed to stand for 3 hours. The white precipitate was removed by filtration and the mother liquors were concentrated under reduced pressure to give a yellow foam. The foam was purified by chromatography (flash column made with grade III neutral alumina and eluted with a gradient of 0-1% ethanol in dichloromethane) to give the title compound (350 mg) as a colourless oil which was crystallised from cyclohexane to give colourless prisms; mp 102°-104° C.; Microanalysis, found: C,63.5; H,8.1; N, 15.5%; C19H28N4O3 requires C,63.3; H,7.8; N,15.5%; NMR (d6DMSO+CD3COOD): 1.2 (t,3H), 1.3-1.7 (m,2H), 1.8 (m,2H), 2.5-2.8 (m,6H), 3.0-3.4 (m,3H), 3.6 (br s,4H), 3.9 (d,1H), 4.0 (q,2H), 4.2 (d,1H), 7.1 (d,2H), 8.2 (d,2H); m/e 361 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C1COCC1.CC([O-])(C)C.[K+].CS([C:31]1[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][N:32]=1)(=O)=O>O>[CH3:40][S:37]([C:34]1[CH:35]=[CH:36][C:31]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:15])=[CH:6][CH:7]=2)=[N:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(C(=O)c3ccccc3)cc2)nc1

Procedure:
To 5.5 g of p-hydroxybenzophenone in a 25 ml THF/25 ml DMSO mixture was added 3.6 g of t-BuOK and then 6.51 g of 2,5-bis(methylsulfonyl)pyridine, and the resulting mixture was heated at 62° C. for 11/2 hrs. The reaction mixture was cooled and added to approximately 3 to 4 volumes of water and stirred. The crude product which formed was filtered and dried. Recrystallization from ethanol gave purified (4-((5-(methylsulfonyl)-2-pyridinyl)oxy)phenyl)phenylmethanone, m.p. 130°-131.5° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][C:11]([OH:13])=O.[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21])[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH:21][C:11](=[O:13])[CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: O=C(O)Cc1cc2ccccc2o1
Reactant: CC(C)COC(=O)[C@H](C)N
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1cc2ccccc2o1

Procedure:
Following General Procedure I′ above, and using benzofuran-2-ylacetic acid (Maybridge) and alanine iso-butyl ester (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: I.[NH2:2][CH:3]([S:10][CH3:11])/[N:4]=[C:5](/N(C)C)\[CH3:6].Cl[C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>ClCCl>[CH3:6][C:5]1[N:4]=[C:3]([S:10][CH3:11])[NH:2][C:13](=[O:20])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CSC(N)/N=C(\C)N(C)C
Agent: I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nc(SC)[nH]c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
To a solution of (1E)-N′-[amino(methylthio)methyl]-N,N-dimethylethanimidamide hydrogen iodide salt (73.0 g, 0.26 mole) in dry dichloromethane (900 mL), was added ethyl 3-chloro-3-oxopropanoate (44 mL, 95% Lancaster, 0.34 mole) was added under a nitrogen atmosphere. The mixture was stirred for 4 h at room temperature, cooled to 0° C. then triethylamine (107 mL, 0.78 mole) was added. The reaction mixture was stirred overnight. The solvent was removed and H2O was added. The pH was adjusted to pH=5.0 with acetic acid and extracted with ethylacetate then evaporated and crystallized from the appropriate solvent (Ethylacetate-Hexanes mixture solvent, approximately 20% ethylacetate-Hexanes). This afforded ethyl 4-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (36.5 g, 62% yield) after drying under vacuum.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:34])[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH:16]=1)[CH:9]=[CH:8][C:7]=2[CH3:33])#[N:2].[N-:35]=[N+:36]=[N-:37].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH3:33][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH:16]=2)=[C:11]2[C:6]=1[NH:5][C:4](=[O:34])[C:3]([C:1]1[NH:37][N:36]=[N:35][N:2]=1)=[CH:12]2
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c2cc(C#N)c(=O)[nH]c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c2cc(-c3nnn[nH]3)c(=O)[nH]c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
A liquid mixture of 0.822 g (1.84 mmol) of the 3-cyano-8-methyl-5-[3-(2-quinolinylmethoxy)benzyloxy]-1,2-dihydroquinolin-2-one obtained in Example 3, 0.359 g (5.52 mmol) of NaN3, 0.295 g (5.52 mmol) of NH4Cl and 20 ml of DMF was stirred at a bath temperature of 120° C. for 8 hours. The solvent was distilled off and the residue was dissolved in a large amount of a CHCl3 --MeOH mixed solvent. The solution was washed with water and then dried over MgSO4. The solvent was distilled off, whereby 0.519 g of the title compound was obtained as pale yellow powder (yield: 57.5%).
Reaction SMILES: C(O[C:4]([CH:6]1[C:14](=[O:15])[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]1=[O:16])=[O:5])C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:25][C:4]([CH:6]2[C:14](=[O:15])[C:13]3[N:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]2=[O:16])=[O:5])[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(N)c1
Reactant: CCOC(=O)C1C(=O)c2cccnc2C1=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1cccc(NC(=O)C2C(=O)c3cccnc3C2=O)c1
Temperature: 25 °C

Procedure:
5,7-Dioxo-6,7-dihydro-5H-[1]pyrindine-6-carboxylic acid ethyl ester (100 mg) (see D. Binder, Monatshefte für Chemie, Vol. 105, Pp. 179-186, 1974), m-anisidine (0.124 ml) and acetic acid (0.052 ml) were suspended in toluene (5 ml). This mixture was refluxed for 2 hours under nitrogen. The mixture was cooled to room temperature and the ppt was collected with suction. The ppt was washed with toluene and dichloromethane and dried under reduced pressure to give a brown powder (112 mg). ESI−MS: m/z 297 (MH+); 1H-NMR (DMSO-d6): δ3.74 (3H, s), 6.54 (1H, dd, J=8.5 Hz, J=2.5 Hz), 7.04 (1H, bd, J=8.5 Hz), 7.16 (1H, t, J=8.5 Hz), 7.38 (1H, dd, J=7.0 Hz, 4.5 Hz), 7.44 (1H, t-like, 2.5 Hz), 7.70 (1H, dd, J=7.0 Hz, 1.5 Hz), 8.57 (1H, dd, J=4.5 Hz, 1.5 Hz), 10.79 (1H, s).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[Br:31][C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:39]([NH:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([Br:31])[CH:33]=4)=[O:40])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: O=C=Nc1cccc(Br)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Br)c1)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 42.3 mg (0.21 mmol) of 3-bromophenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 43 mg (75.1% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:18])[NH:9][C:10]2[CH:14]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[O:12][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Cl:26])C(=O)C1>CC(O)=O.O.C(OCC)(=O)C>[C:1]1([O:7][C:8](=[O:18])[NH:9][C:10]2[C:14]([Cl:26])=[C:13]([CH:15]3[CH2:17][CH2:16]3)[O:12][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1cc(C2CC2)on1)Oc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(Nc1noc(C2CC2)c1Cl)Oc1ccccc1
Temperature: 79 °C

Procedure:
(5-Cyclopropyl-isoxazol-3-yl)-carbamic acid phenyl ester (0.25 g, 1.024 mmol) is dissolved in AcOH (7.31 mL) and NCS (0.205 g, 1.53 mmol) is added and the reaction is heated to 79° C. for 2 hours. The reaction is cooled to room temperature and diluted with water and ethyl acetate. The organic layer is washed with 500 mL of water to remove the acid. The organic layer is dried (sodium sulfate) and concentrated to an oil (352 mg) to obtain the title compound that is used without further purification. MS (ESI) m/z 279.00 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.Cl.[C:11]1([C:17]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:25]3[CH:21]([CH2:22][NH:23][CH2:24]3)[C:20](=[O:26])[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:27]1([C:17]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:25]3[CH:21]([CH2:22][N:23]([C:7](=[O:9])[CH2:6][C:3]4[CH:4]=[CH:5][S:1][CH:2]=4)[CH2:24]3)[C:20](=[O:26])[CH2:19][CH2:18]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)Cc1ccsc1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccsc3)CC12
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-(3-thienyl)acetic acid (0.99 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 15 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.24 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred for 16 hours at 20° C., then washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from a mixture of acetonitrile (30 cc) and isopropyl ether (40 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[2-(3-thienyl)acetyl]-4-perhydroisoindolone (2.2 g) melting at 224° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][C:25](=O)[CH3:26])[CH:20]=[CH:21][CH:22]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:25]([CH3:26])[CH2:24][CH2:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:28])[F:29])[CH:18]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)CCc1cccc(C(F)(F)F)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(3-trifluoromethyl-phenyl)-butan-2-one.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[C:8]([CH3:17])[CH:9]=[C:10]([N+:14]([O-])=O)[C:11]=2[CH3:13])[N:6]=[CH:5][CH:4]=1)#[N:2].C(O)C.[OH-].[Na+]>O>[NH2:14][C:10]1[C:11]([CH3:13])=[C:12]2[C:7](=[C:8]([CH3:17])[CH:9]=1)[N:6]=[CH:5][CH:4]=[C:3]2[C:1]#[N:2]
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c(C#N)ccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(N)c(C)c2c(C#N)ccnc12
Temperature: 60 °C

Procedure:
A mixture of 4-cyano-5,8-dimethyl-6-nitroquinoline (2.54 g, 11.2 mmol), stannous chloride dihydrate (12.6 g, 55.9 mmol) and ethanol (200 mL) is heated at 60° C. for 1.5 hours. The reaction is cooled to room temperature, and water (60 mL) is added. The mixture is basified with 10% aqueous sodium hydroxide solution (70 mL) and subsequently extracted with methylene chloride (3×150 mL). Drying (sodium sulfate) and evaporation provides 6-amino-4-cyano-5,8-dimethylquinoline.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:34](N)([NH2:37])(=[O:36])=[O:35]>CC(O)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:21][CH2:22][N:23]([S:34](=[O:36])(=[O:35])[NH2:37])[CH2:24][CH2:25]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(N)(=O)=O
Reactant: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Solvent: CC(C)O
Product: NS(=O)(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Yield: 51.2 %

Procedure:
A mixture of the compound obtained in Example 66 (391 mg, 0.80 mmol), sulfamide (1.54 g, 16.0 mmol), 2-propanol (20 mL) and distilled water (10 mL) was stirred under reflux for 4 days. The reaction mixture was concentrated under reduced pressure, and to the concentrate was added a saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted with, dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1), and the desired fraction was concentrated under reduced pressure. To the concentrate were added diethyl ether and ethyl acetate, and the resulting precipitates were collected by filtration. The precipitates were washed with diethyl ether, and dried under reduced pressure to give the titled compound (230 mg, 0.41 mmol, Yield 51%) as white crystals.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[O:6][C:7]([CH3:20])=[CH:8][C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.I[CH3:22]>CN(C=O)C>[CH3:22][O:3][CH2:4][C:5]1[O:6][C:7]([CH3:20])=[CH:8][C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CI
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(CO)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1oc(C)cc(=O)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a suspension of sodium hydride (0.48 g, 20 mmol, 2 eq.) in 30 ml dry DMF was added 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one (2.46 g, 10 mmol, 1 eq.) followed by dropwise addition of iodomethane (4.26 g, 30 mmol, 3 eq.) at 0° C. under nitrogen. After stirring for 30 minutes at this temperature, the reaction mixture was poured into ice cold water (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic fractions were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to yield the crude product (2.6 g,˜100%) as an orange oil which solidified on cooling. Recrystallisation from CH2Cl2/Pet. ether 40/60 afforded the pure product (2.35 g, 90%) as a white crystalline solid. m.p. 30-32° C.